Implantation is the final frontier to embryogenesis and successful pregnancy. Over the past three decades, there have been tremendous advances in the understanding of human embryo development. Since the advent of In Vitro Fertilization, the embryo has been readily available to study outside the body. Indeed, the study has led to much advancement in embryonic stem cell derivation. Unfortunately, it is not so easy to evaluate the steps of implantation since the uterus cannot be accessed by most research tools. This has limited our understanding of early implantation. Both the physiological and pathological mechanisms of implantation occur largely unseen. The heterogeneity of these processes between species also limits our ability to develop appropriate animal models to study. In humans, there is a precise coordinated timeline in which pregnancy can occur in the uterus, the so called “window of implantation”. However, in many cases implantation does not occur despite optimal timing and embryo quality. It is very frustrating to both a patient and her clinician to transfer a beautiful embryo into a prepared uterus only to have it fail to implant. This chapter will review the mechanisms of human embryo implantation and discuss some reasons why it fails to occur.